Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives

ABSTRACT

This invention discloses a process for the preparation of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives which comprises conducting an intramolecular cyclization reaction of the compounds of formulas II III in an acid medium. ##STR1##

The present invention relates to a new and improved process for thepreparation of(±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino-4H-pyrazino[2,1-a]isoquinolinederivatives.

The compounds of the present invention are represented by the followinggeneral structural formula I: ##STR2## wherein R₁ is hydrogen, aloweralkyl or R₄ CO ; and R₂ and R₃ are independently hydrogen, aloweralkyl and alkoxy; and R₄ is hydrogen, a loweralkyl, cycloalkyl oraryl.

As used herein the term "loweralkyl" means a straight or branched chainC₁ -C₆ alkyl.

The term "alkoxy" means a straight or branched chain C₁ -C₆ alkoxy.

The term "cycloalkyl" means a cycloalkyl having 3 to 6 membered ring(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like).

The term "aryl" means phenyl or a phenyl optionally substituted by oneor more radicals selected from the group consisting of a C₁ -C₆ alkyl,halogen, nitro or C₁ -C₆ alkoxy.

Certain compounds of formula I are known compounds or exhibitanthelmintic activity against schistosomes.

The compounds of formula I described herein have been prepared byvarious methods known to the prior art.

In one prior art process described in U.S. Pat. No. 3,993,760 (1976),the compounds of formula I are prepared by cyclization of1-(N-acylaminomethyl)-2-halomethylcarboxy-1,2,3,4-tetrahydroisoquinoline.

Similar and other processes are also described in DOS Nos. 2,457,971(1976) and 2,504,250 (1976) and Experientia 33, 1036 (1977).

The prior art processes described in above literatures have certaininherent disadvantages. For instance, the process disclosed in U.S. Pat.No. 3,993,760 (1976) requires high pressure catalytic hydrogenation athigh temperature (˜100° C.) to produce the starting material,1-aminomethyl-1,2,3,4-tetrahydroisoquinoline, from1-cyano-2-acyl-1,2,-dihydroisoquinoline. Other processes described inDOS Nos. 2,457,971 and 2,504,250 (1976) and Experientia 33, 1036 (1977)are not economically attractive for industrial application.

It is therefore an object of the present invention to overcome thesedisadvantages associated with the prior art processes.

It is another object of this invention to provide a simple andeconomical process for the production of the compound of formula I inlarge scale.

The present invention relates to the discovery of a novel process forthe preparation of the compounds of formula I, which comprisesconducting an intramolecular cyclization reaction of the compoundsrepresented by the following structural formulas II or III: ##STR3##wherein R₁, R₂, R₃ and R₄ are as defined above and R₅ is methyl, ethylor both R₅ groups together form a methylene group.

The important novelty of this invention is to form isoquinoline andpiperazine ring simultaneously or stepwise by an intramolecularcyclization reaction.

In accordance with the process of the present invention, the compoundsof formula II, wherein R₁ is an acyl substituent, can be converted intothe compounds of formula I directly or, if desired, via theintermediates of formula IV or V, below, which can be isolated undercertain reaction conditions. ##STR4##

The compounds of formula III also can be converted to the compounds offormula I directly or via the intermediates of formula V.

The process of the present invention is expediently carried out in anacid medium. An excess of the acid can be used as solvent or thereaction can be carried out in the presence of an organic solvent.

Suitable acids for use in the process of the present invention includesulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid(PPA), formic acid, acetic acid, trichloroacetic acid, trifluoroaceticacid, methanesulfonic acid, p-toluenesulfonic acid and boron trifluorideetherate.

Suitable organic solvents include dichloromethane, chloroform,carbontetrachloride, 1,2-dichloroethane, methanol, ethanol, isopropanol,1,4-dioxane, tetrahydrofuran (THF), diethyl ether, ethylene glycol,dimethyl ether and acetonitrile.

The one-step conversion of the compounds of formula II or III into thecompounds of formula I is preferably carried out in a strong acid mediumwithout solvent at a temperature from 20° C. to 40° C. Concentratedsulfuric acid or methansulfonic acid is prefered. The reaction isusually complete in about 2 to 8 hours.

In the two-step case when the cyclization reaction of the compounds offormula II or III is carried out in the presence of catalytic amount ofan acid with an organic solvent as hereinabove mentioned the compoundsof formula V are isolated in excellent yield.

Also, the compounds of formula IV are isolated when the compound offormula II, wherein R is an acycl substituent, is treated with a strongacid at low temperature, preferable at 10° C. to 20° C. for about 30minutes, and then added to an aqueous alkaline medium.

The further cyclization reaction of the compounds of formula IV or V tothe compounds of formula I is carried out in a strong acid medium aspreviously mentioned in the preparation of the compound formula I fromthe compounds of formula II or III. Usually the reaction is carried outwithout solvent at about room temperature.

The intramolecular cyclization reaction in this invention can betheoretically supported by the similar reaction described in theliteratures [Tet. Let. No. 44, 4493 (1972) and ibid, No.11, 935 (1977)].

The compound of formula I wherein R₁ is an acyl substituent can beprepared by acylation of the compound of formula I, wherein R₁ ishydrogen, with a corresponding acylchloride or an acid anhydride.

The starting material, the compound of formula II, may be prepared bysimply reacting N-(2-phenyl)ethylmonochloroacetamide [JACS 55, 2555(1933)] with N-substituted or unsubstituted aminoacetaldehydedialkylacetal.

The compound of formula III may be prepared by treating theN-(2,2-dialkoxy)ethylphenethylamine (prepared from phenethylamine andchloro or bromoacetaldehyde dialkylacetal) with N-acylglycine.

The following examples further illustrate the present invention, butthey are not constructed to limit the scope of the invention.

EXAMPLE 1(±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (I; R₁═R₂ ═R₃ ═H)

22.6 g of N-(2-phenyl)ethyl-α-N-(2,2-dimethoxy)ethylglycine amide (II;R₁ ═R₂ ═R₃ ═H, R₅ ═CH₃) was added to 40 ml of concentrated sulfuric acidwith cooling. The mixture was stirred at room temperature for 3 hours.After completion of the reaction, the resultant mixture was poured intoice-water, and then neutralized with ˜20% aqueous sodium hydroxide withcooling. The neutralized solution was extracted with diethyl ether, andthe ether extract was concentrated to give 12.3 g (61%) of the product,m.p. 118°˜120° C.

EXAMPLE 2(±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (I; R₁═R₂ ═R₃ ═H)

To a mixture of 10 ml of concentrated sulfuric acid and 5 ml ofacetonitrile was added 2.7 g ofN-(2-phenyl)ethyl-α-N-(2,2-dimethoxy)ethylglycine amide (II; R₁ ═R₂ ═R₃═H, R₅ ═CH₃). The resultant mixture was stirred at room temperature for5 hours. The reaction mixture was worked up by the same procedure as inExample 1 to give 1.8 g (89%) of the product.

When diethyl ether is used as solvent instead of the acetonitrile, thereaction gives the same result.

EXAMPLE 3(±)-2-cyclohexanecarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline(I; R₁ ═cyclohexanecarbonyl, R₂ ═R₃ ═H)

3.76 g (0.01 mol) ofN-(2-phenyl)ethyl-α-[N-(2,2-dimethoxy)ethyl-N-cyclohexanecarbonyl]glycineamide (II; R₁ ═cyclohexanecarbonyl, R₂ ═R₃ ═H, R₅ ═methyl) was added to20 ml of methanesulfonic acid and the resultant mixture was stirred atroom temperature for 8 hours. The reaction mixture was concentrated invacuo, and then the residue was diluted with water and neutralized with˜10% aqueous sodium hydroxide solution. The neutralized solution wasextracted with dichloromethane, and the extract was concentrated. Theresidue was recrystallized with ethyl acetate to give 1.9 g (61%) of theproduct, m.p. 133°˜134° C.

EXAMPLE 4(±)-2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline(I; R₁ ═benzoyl, R₂ ═R₃ ═H)

A solution of 3.7 g ofN-(2-phenyl)ethyl-α-[N-(2,2-dimethoxy)ethyl-N-benzoyl]glycine amide in 5ml of diethyl ether was added slowly to 10 ml of concentrated sulfuricacid. The mixture was stirred at room temperature for 7 hours. Aftercompletion of the reaction, the resultant mixture was poured intoice-water and neutralized with aqueous alkali. The resultant solutionwas extracted with diethyl ether, and then the ether extract wasconcentrated. The residue was recrystallized with ethyl acetate to give1.8 g (68%) of the product, m.p. 162°˜163° C.

EXAMPLE 5 1-(2-phenyl)ethyl-4-acetyl-2-hydroxypiperazine-6-one (IV; R₁═acetyl, R₂ ═R₃ ═H)

To 5 ml of concentrated sulfuric acid was added 3.08 g ofN-(2-phenyl)ethyl-α-[N-(2,2-dimethyoxy)ethyl-N-acetyl]glycine amide (II;R₁ ═acetyl, R₂ ═R₃ ═H, R₅ ═methyl). The mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was slowly added to˜10% aqueous sodium hydroxide solution with cooling. The resultantmixture was extracted with dichloromethane, and then the extract wasconcentrated. The residue was recrystallized with ethyl acetate-hexaneto give the 2.4 g (92%) of the product, m.p. 128°˜129° C. nmr(CDCl₃)δ:2.05(s,3,COCH₃), 2.65-4.80(m,10, CH₂, CH), 7.20(s,5, phenyl ringportions), IR(KBr)cm⁻¹ : 3350(s,OH), 2930(m, CH), 1650(s, CO),1420-1480(s), 1170(s)

EXAMPLE 61-(2-phenyl)ethyl-4-cyclohexanecarbonyl-2,3-dehydropiperazine-6-one (V;R₄ ═cyclohexyl, R₂ ═R₃ ═H)

To a solution of 4.0 g ofN-(2-phenyl)ethyl-N-(2,2-diethoxy)ethyl-α-N-cyclohexanecarbonylglycineamide (III; R₄ ═cyclohexyl, R₂ ═R₃ ═H, R₅ ═ethyl) in 10 ml ofdichloromethane was added 1 ml of methanesulfonic acid. The mixture wasstirred at room temperature for 3 hours. The reaction mixture was washedwith aqueous alkaline solution, and then the organic layer wasconcentrated. The residue was recrystallized with ethyl acetate-hexaneto give 2.8 g (90%) of the product, m.p. 128°˜130° C. nmr(CDCl₃)δ:0.85-2.0(m, 10, cyclohexane ring protons), 2.90(t, 2, CH₂), 3.70(t, 2,CH₂), 4.20(s, 2, CH₂), 5.30(d, 1, vinyl proton), 6.00(d, 1, vinylproton), 7.10(s, t, phenyl ring protons), IR(KBr)cm⁻¹ : 2930(m, CH),1660(s, CO), 1450, 1400(m), 1300(m), 1000(m), 700(w).

EXAMPLE 7(±)-2-cyclohexanecarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline(I; R₁ ═cyclohexanecarbonyl, R₂ ═R₃ ═H)

3.3 g of1-(2-phenyl)ethyl-4-cyclohexanecarbonyl-2-hydroxypiperazine-6-one (V; R₂═R₃ ═H, R₁ ═cyclohexanecarbonyl) was slowly added to 5 ml ofconcentrated sulfuric acid. The mixture was stirred at room temperaturefor 3 hours. The reaction mixture was poured into ice-water andneutralized with aqueous alkali. The resultant mixture was extractedwith dichloromethane, and then the extract was concentrated. The residuewas recrystallized with ethyl acetate to give 3.0 g (95%) of theproduct, m.p. 132°˜134° C.

EXAMPLE 8(±)-2-acetyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline(I; R₁ ═acetyl, R₂ ═R₃ ═H)

To a solution of 3.4 g ofN-(2-phenyl)ethyl-N-(2,2-diethoxy)ethyl-α-N-acetylglycine amide (III; R₂═R₃ ═H, R₄ ═methyl) in 10 ml of 1,2-dichloroethane was added 3 ml ofmethanesulfonic acid. The mixture was refluxed for 8 hours. Aftercompletion of the reaction, the resultant mixture was washed withaqueous alkali, and then the organic layer was concentrated. The residuewas recrystallized with ethyl acetate to give 2.1 g (86%) of theproduct, m.p. 144°˜145° C.

EXAMPLE 91-(2-phenyl)ethyl-4-cyclohexanecarbonyl-2,3-dehydropiperazin-6-one (V;R₂ ═R₃ ═H, R₄ ═cyclohexyl)

3.8 g of N-(2-phenyl)ethyl-α-[N-(2,2-dimethoxy)ethyl-Ncyclohexanecarbonyl]glycine amide (II; R₁ ═cyclohexanecarbonyl, R₂ ═R₃═H, R₅ ═methyl) was added to 5 ml of 20% hydrochloric acid, and then themixture was stirred at room temperature for 3 hours. After completion ofthe reaction, the resultant solid was collected by filtration to give2.9 g (93%) of the product, m.p. 129 131° C.

EXAMPLE 10(±)-4-oxo-9,10-dimethoxy-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline(I; R₁ ═H, R₂ ═R₃ ═OCH₃)

2.16 g ofN-[2-(3,4-dimethoxyphenyl)ethyl]-α-N-(2,2-dimethoxy)ethylglycine amide(II; R₁ ═H, R₂ ═R₃ ═OCH₃, R₅ ═CH₃) was added to 2 ml of concentratedsulfuric acid at 0° C. The mixture was stirred at room temperature for1.5 hours. The resultant mixture was poured into ice-water andneutralized with aqueous alkali to PH=˜8. The neutralized solution wasextracted with dichloromethane, and then the extract was concentrated.The residue was recrystallized with ethyl acetate to give 1.5 g (96%) ofproduct, m.p. 136°˜137° C. nmr(CDCl₃)δ: 2.0(s,1, NH), 2.30˜3.10(m, 4,CH₂), 3.30˜4.00(m, 3, CH₂ and CH), 3.8(s, 6, OCH₃), 4.40˜5.00(m, 2,CH₂), 6.5(s, 2, phenyl ring protons)

EXAMPLE 11(±)-2-(p-chlorobenzoyl)-4-oxo-9,10-dimethyoxy-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline(I; R₁ ═p-chlorobenzoyl, R₂ ═R₃ ═OCH₃)

To a solution of 2.62 g of(±)-4-oxo-9,10-dimethoxy-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline(I; R₁ ═H, R₂ ═R₂ ═OCH₃) in 10 ml of dichloromethane was added 2 ml oftriethylamine, and then 1.9 g of p-chlorobenzoyl chloride was slowlyadded 0°˜5° C. The resultant mixture was stirred at 10° C. for 1.5hours. To the reaction mixture was added water, and the organic layerwas seperated. The organic extract was concentrated, and then theresidue was triturated with ethyl acetate-ether to obtain 4.0 g (˜100%)of the product, m.p. 139°˜140° C.

EXAMPLE 12N-[2-(3,4-dimethoxyphenyl)ethyl]-α-N-(2,2-dimethoxy)ehtylglycine amide(II, R₁ ═H, R₂ ═R₃ ═OCH₃)

12.86 g of N-(3,4-dimethoxyphenyl)ethylmonochloroacetamide and 11.6 g ofaminoacetaldehyde dimethylacetal were added to 10 ml of toluene, and themixture was refluxed for 40 minutes. After cooling the reaction mixture,the resultant solid was filtered off. The filtrate was washed withwater, and then the toluene solution was concentrated to give a viscousoil (16.19 g, 99.3%), HCl salt m.p. 98°˜99° C. The invention being thusdescribed, it will be obvious that the same may be varied in many ways.Such variations are not to be regarded as a departure from the spiritand scope of the invention, and all such modifications as would beobvious to one skilled in the art are intended to be included within thescope of the following claims.

What is claimed is:
 1. A process for the production of(±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolines offormula I: ##STR5## which comprises an intramolecular cyclizationreaction of a compound of formula II or III, in an acid medium, whereinsaid acid is at least one member selected from the group consisting ofsulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid(PPA), formic acid, acetic acid, trichloroacetic acid, trifluoroaceticacid, methanesulfonic acid, p-toluene-sulfonic acid and borontrifluoride etherate, with or without organic solvent, ##STR6## whereinR₁ represents hydrogen, a loweralkyl or R₄ CO; R₂ and R₃ eachindependently represent hydrogen, a loweralkyl or alkoxy; R₄ representshydrogen, a loweralkyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl or phenyl substituted by one or more of the radicalsselected from the group consisting of C₁ -C₆ alkyl, halogen, nitro andC₁ -C₆ alkoxy, and R₅ represents methyl, ethyl or methylene.
 2. Theprocess according to claim 1 wherein said acid is selected from thegroup consisting of sulfuric acid, hydrochloric acid, phosphoric acid,polyphosphoric acid (PPA), formic acid, acetic acid, trichloroaceticacid, trifluoroacetic acid, methanesulfonic acid, p-toluene-sulfonicacid and boron trifluoride etherate.
 3. The process according to claim 1wherein when the organic solvent is present, said organic solvent isselected from the group consisting of dichloromethane, chloroform,carbontetrachloride, 1,2-dichloroethane, methanol, ethanol, isopropanol,1,4-dioxane, tetrahydrofuran(THF), diethyl ether, ethylene glycoldimethyl ether and acetonitrile.
 4. The process according to claim 1wherein the cyclization reaction of the compounds of formula II, whereinR₁ is R₄ CO, is effected in the presence of an acid and organic solventby a two-step reaction via the intermediate compound of formula IV:##STR7## wherein R₁ represents R₄ CO; and R₂ and R₃ independentlyrepresent hydrogen, a loweralkyl or alkoxy; and R₄ represents hydrogen,a loweralkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenylor phenyl substituted by one or more of the radicals selected from thegroup consisting of C₁ -C₆ alkyl, halogen, nitro and C₁ -C₆ alkoxy. 5.The process according in claim 1 wherein the cyclization reaction of thecompounds of formula II or III are effected in the presence of an acidand organic solvent by a two-step reaction via the intermediate compoundof formula V: ##STR8## wherein R₂ and R₃ represent independentlyhydrogen, a loweralkyl, or alkoxy; and R₄ represents hydrogen, aloweralkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl orphenyl substituted by one or more of the radicals selected from thegroup consisting of C₁ -C₆ alkyl, halogen, nitro and C₁ -C₆ alkoxy. 6.The method of claim 1 wherein the conversion is effected without asolvent at a temperature of from 20°-40° C.
 7. The method of claim 4wherein the acid treatment of said compounds of formula II is effectedat a temperature of 10°-20° C.
 8. A process for the production of(±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolines offormula I: ##STR9## which comprises an intramolecular cyclizationreaction of a compound of formula II, in an acid medium, wherein saidacid is at least one member selected from the group consisting ofsulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid(PPA), formic acid, acetic acid, trichloroacetic acid, trifluoroaceticacid, methanesulfonic acid, p-toluene-sulfonic acid and borontrifluoride etherate, with or without organic solvent, ##STR10## whereinR₁ represents hydrogen, a loweralkyl or R₄ CO; R₂ and R₃ eachindependently represent hydrogen, a loweralkyl or alkoxy; R₄ representshydrogen, a loweralkyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl or phenyl substituted by one or more of the radicalsselected from the group consisting of C₁ -C₆ alkyl, halogen, nitro andC₁ -C₆ alkoxy, and R₅ represents methyl or ethyl or both R₅ groupstogether form a methylene group.
 9. The process according to claim 8wherein the cyclization reaction of the compounds of formula II iseffected in the presence of an acid and organic solvent by a two-stepreaction via the intermediate compound of formula V: ##STR11## whereinR₂ and R₃ represent independently hydrogen, a loweralkyl, or alkoxy; andR₄ represents hydrogen, a loweralkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl or phenyl substituted by one or more ofthe radicals selected from the group consisting of C₁ -C₆ alkyl,halogen, nitro and C₁ -C₆ alkoxy.
 10. The process according to claim 8wherein when the organic solvent is present, said organic solvent isselected from the group consisting of dichloromethane, chloroform,carbontetrachloride, 1,2-dichloroethane, methanol, ethanol, isopropanol,1,4-dioxane, tetrahydrofuran (THF), diethyl ether ethylene glycoldimethyl ether and acetonitrile.
 11. The process according to claim 8,wherein the cyclization reaction of the compounds of formula II whereinR₁ is R₄ CO, is effected in the presence of an acid and organic solventby a two-step reaction via the intermediate compound of formula IV:##STR12## wherein R₁ represents R₄ CO; and R₂ and R₃ independentlyrepresent hydrogen, a loweralkyl or alkoxy; and R₄ represents hydrogen,a loweralkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenylor phenyl substituted by one or more of the radicals selected from thegroup consisting of C₁ -C₆ alkyl, halogen, nitro and C₁ -C₆ alkoxy. 12.The method of claim 1, wherein said lower alkyl is a straight orbranched chain C₁ -C₆ alkyl and said alkoxy is a straight or branchedchain C₁ -C₆ alkoxy.
 13. The method of claim 4, wherein said lower alkylis a straight or branched chain C₁ -C₆ alkyl and said alkoxy is astraight or branched chain C₁ -C₆ alkoxy.